Thiazole derivatives

ABSTRACT

Compounds of the formula (I), in which R 1 , R 2 , R 3 , R 4 , K, G, E and W

BACKGROUND OF THE INVENTION

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

The present invention relates to compounds and to the use of compoundsfor the treatment of diseases which are accompanied by an increase inthe lysophosphatidic acid level, furthermore to pharmaceuticalcompositions which comprise these compounds.

In detail, the present invention relates to compounds of the formula I,which preferably inhibit one or more enzymes which regulate and/ormodulate the lysophosphatidic acid (LPA) level, to compositions whichcomprise these compounds, and to processes for the use thereof for thetreatment of diseases and complaints, such as angiogenesis, cancer,tumour formation, growth and propagation, arteriosclerosis, oculardiseases, choroidal neovascularisation and diabetic retinopathy,inflammatory diseases, arthritis, neurodegeneration, restenosis, woundhealing or transplant rejection. In particular, the compounds accordingto the invention are suitable for the therapy or prophylaxis of cancerdiseases.

Autotaxin (ATX) is an enzyme which is responsible for the increase inthe lysophosphatidic acid level in ascites and plasma (Xu et al. 1995,Clinical Cancer Research Vol. 1, page 1223 and Xu et al. 1995, Biochem.J. Vol-309, page 933). ATX converts lysophatidylcholine (LPC) intolysophosphatidic acid (Tokumura et at. 2002, J. Biol. Chem., Vol 277,page 39436 and Umezu-Gozo et al. 2002, J. Biol. Chem., Vol. 158, page227) LPA is an intercellular lipid mediator which influences amultiplicity of biological and biochemical processes, such as, forexample, smooth muscle contraction, thrombocyte aggregation andapoptosis (Tigyi et al. 2003 Prog. Lipid Res. Vol 42, page. 498 andMills et al. 2003 Nat. Rev. Cancer Vol. 3, page 582 and Lynch et al.2001 Prost. Lipid Med. Vol. 64, page 33). In addition, LPA can be foundin increased concentrations in plasma and ascites fluid from ovariancancer patients in the early and late phase. LPA plays a role there intumour cell proliferation and invasion thereof into neighbouring tissue,which can result in metastasisation (Xu et al. 1995, Clinical CancerResearch Vol. 1, page 1223 and Xu et al. 1995, Biochem. J. Vol-309, page933). These biological and phatobiological processes are switched on bythe activation by LPA of G-protein-coupled receptors (Cantos et al.2000, Mol. Pharm. Vol 58, page. 1188).

For this reason, it is desirable to lower the LPA level for thetreatment of tumour patients. This can be achieved by the inhibition ofenzymes which are involved in LPA biosynthesis, such as, for example,autotaxin (ATX, Sano et al. 2002, J. Biol. Chem. Vol. 277, page 21197and Aoki et al. 2003, J. Biol. Chem. Vol. 277 page 48737). Autotaxinbelongs to the enzyme family of the nucleotides pyrophosphatases andphosphodiesteraces (Goding et al. 1998, Immunol. Rev. Vol. 161, page 11)and represents an important starting point in antitumour therapy (Millset al. 2003 Nat. Rev. Cancer Vol. 3, page 582 and Goto et al. 2004 J.Cell. Biochem. Vol. 92, page 1115) since it is expressed to an increasedextent in tumours and causes tumour cell proliferation and invasionthereof into neighbouring tissue, which can result in metastasisation(Nam et al. 2000, Oncogene, Vol. 19 page 241). In addition, autotaxintogether with other angiogenetic factors causes blood vessel formationin the course of angiogenesis (Nam et al. 2001, Cancer Res, Vol. 61page. 6938). Angiogenesis is an important process in tumour growth,which ensures supply of the tumour with nutrients. For this reason,inhibition of angiogenesis is an important starting point in cancer andtumour therapy, in which it is intended to starve the tumour (Folkman,2007, Nature Reviews Drug Discovery Vol. 6, page 273-286).

Surprisingly, it has been found that the compounds according to theinvention cause specific inhibition of the enzyme family of thenucleotides pyrophosphatases and phosphodiesterases, in particularautotaxin. The compounds according to the invention preferably exhibitan advantageous biological activity, which can easily be detected in theassays described, for example, herein. In assays of this type, thecompounds according to the invention preferably exhibit and cause aninhibiting effect, which is usually documented by IC₅₀ values in asuitable range, preferably in the micromolar range and more preferablyin the nanomolar range.

In general, all solid and non-solid tumours can be treated with thecompounds of the formula I, such as, for example, monocytic leukaemia,brain, urogenital, lymphatic system, stomach, laryngeal and lungcarcinoma, including lung adenocarcinoma and small-cell lung carcinoma.Further examples include prostate, pancreatic and breast carcinoma.

As discussed herein, effects of the compound according to the inventionare relevant for various diseases. Accordingly, the compounds accordingto the invention are useful in the prophylaxis and/or treatment ofdiseases which are influenced by inhibition of one or more nucleotidespyrophosphatases and/or phosphodiesterases, in particular autotaxin.

The present invention therefore relates to compounds according to theinvention as medicaments and/or medicament active ingredients in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical agent for the treatment and/or prophylaxis of the saiddiseases, and also to a method for the treatment of the said diseasescomprising the administration of one or more compounds according to theinvention to a patient in need of such administration.

It can be shown that the compounds according to the invention have anadvantageous action in a xenotransplant tumour model.

The host or patient can belong to any mammalian species, for example aprimate species, in particular humans; rodents, including mice, rats andhamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

The sensitivity of a certain cell to treatment with the compoundsaccording to the invention can be determined by testing in vitro.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a time which issufficient to enable the active agents to induce cell death or toinhibit migration, usually between approximately one hour and one week.For testing in vitro, cultivated cells from a biopsy sample can be used.The viable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. Typically, a therapeutic dose issufficient to considerably reduce the undesired cell population in thetarget tissue, while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example at least about a 50% reduction in the cell burden,and can be continued until essentially no undesired cells can bedetected in the body.

PRIOR ART

Compounds which are capable of inhibiting autotaxin are described inPeng et al. Bioorganic & Medicinal Chemistry (Letters 17, 2007, page1634-1640). The compounds described therein are lipid analogues, whichdo not have any structural features in common with the compoundsaccording to the invention.

Other thiazole derivatives are described in WO 2007020213, US2006069102, FR 2856685, WO 2004058751, WO 2004058750, WO 9715567.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes a bicyclic unsaturated or aromatic heterocycle having 1    to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di-    or trisubstituted by A, Ar, SR, NR₂, Hal, NO₂, CN,    (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, CONR₂, OR⁵ and/or ═O (carbonyl oxygen),-   R², R³ each, independently of one another, denote H, A, Ar, OR, SR,    NR₂, Hal, NO₂, CN or (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y,-   R⁴ denotes H, Hal, A, OR, NR₂ or (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y,-   X denotes O, NR or CR₂,-   Y denotes OR or NR₂,-   R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5 or    6 C atoms, in which 1-7H atoms may be replaced by F and/or Cl,-   K denotes C═O, CR₂CO or CR₂,-   E denotes COO(CR₂)_(n), CO(CR₂)_(m)O, CONH(CR₂), S(O)_(q)(CR₂)_(n),    CO(CR₂)_(n), (CR₂), CO(CR₂)_(m)O(CR₂)_(p), CO(CR₂)_(m)NH(CR₂)_(p) or    C(═S)O(CR₂)_(n),-   R denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5 or    6 C atoms,-   W denotes Ar or Het,-   G denotes CH or N,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by    Hal, A, (CR₂)_(n)OR, (CR₂)_(n)NR₂, SR, NO₂, CN, COOR, CONR₂, NRCOA,    NRSO₂A, SO₂NR₂, S(O)_(q)A, CO-Het, (CR₂)_(n)Het, O(CR₂)_(n)NR₂,    O(CR₂)_(n)Het, NHCOOA, NHCONR₂, NHCOO(CR₂)_(n)NR₂,    NHCOO(CR₂)_(n)Het, NHCONH(CR₂)_(n)NR₂, NHCONH(CR₂)_(n)Het,    OCONH(CR₂)_(n)NR₂, OCONH(CR₂)_(n)Het, CONR(CR₂)_(n)NR₂,    CONR(CR₂)_(n)Het and/or COA,-   Het denotes a mono-, bi- or tricyclic saturated, unsaturated or    aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A,    (CR₂)_(n)OR, (CR₂)_(n)NR₂, SR, NO₂, CN, COOR, CONR₂, NRCOA, NRSO₂A,    SO₂NR₂, S(O)_(q)A, CO-Het¹, (CR₂)_(n)Het¹, O(CR₂)_(n)NR₂,    O(CR₂)_(n)Het¹, NHCOOA, NHCONR₂, NHCOO(CR₂)_(n)NR₂,    NHCOO(CR₂)_(n)Het¹, NHCONH(CR₂)_(n)NR₂, NHCONH(CR₂)_(n)Het¹,    OCONH(CR₂)_(n)NR₂, OCONH(CR₂)_(n)Het¹, CO-Het^(i), CHO, COA, ═S,    ═NH, ═NA and/or ═O (carbonyl oxygen),-   Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N    and/or O atoms, which may be mono- or disubstituted by A, OA, OH,    Hal and/or ═O (carbonyl oxygen),-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7H atoms may be replaced by OR, CN, NR₂, F and/or Cl and/or in    which one or two non-adjacent CH₂ groups may be replaced by O, NH,    S, SO, SO₂ and/or by CH═CH groups, or    -   cyclic alkyl having 3-7 C atoms,-   m denotes 1, 2, 3, 4, 5 or 6,-   n denotes 0, 1, 2, 3, 4, 5, 6, 7 or 8,-   p denotes 0, 1, 2, 3, 4, 5 or 6,-   q denotes 0, 1 or 2,-   Hal denotes F, Cl, Br or I,    and pharmaceutically usable derivatives, solvates, tautomers, salts    and stereoisomers thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to the patent claims and pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, characterised inthat a compound of the formula II

-   -   in which R¹, R², R³, R⁴, G and K have the meanings indicated in        claim 1,    -   is reacted with a compound of the formula III        L-E-W  III    -   in which    -   E and W have the meanings indicated in claim 1, and    -   L denotes Cl, Br, I or a free or reactively functionally        modified OH group,        and/or a base or acid of the formula I is converted into one of        its salts.

A denotes alkyl and is preferably unbranched (linear) or branched, andhas 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. Alkyl preferably denotesmethyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butylor tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-,1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.

Alkyl very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl. Alkyl also denotes cycloalkyl.

Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cylopentyl,cyclohexyl or cycloheptyl.

R¹ preferably denotes a bicyclic unsaturated or aromatic heterocycleselected from the group

which may be unsubstituted or mono-, di- or trisubstituted by A, Ar, SR,NR₂, Hal, NO₂, CN, (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, CONR₂, OR⁵ and/or ═O(carbonyl oxygen); particularly preferred substituents are A, NR₂,CONR₂, OR⁵ and/or ═O.

R² preferably denotes H or A, such as, for example, methyl.

R³ preferably denotes H.

R⁴ preferably denotes H.

R⁵ preferably denotes H or unbranched or branched alkyl having 1, 2, 3or

4 C atoms, in which 1-5H atoms may be replaced by F.

K preferably denotes CO or CH₂.

E preferably denotes COOCH₂, COOCH₂CH₂, SO₂CH₂CH₂, CONHCH₂, COCH₂O orCOCH₂CH₂.

R preferably denotes H or methyl, particularly preferably H.

Ar preferably denotes phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-,m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, furtherpreferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl, 2,5-dimethyl-4-chlorophenyl, naphthyl orbiphenyl.

Ar furthermore preferably denotes phenyl, naphthyl or biphenyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by Hal, A,(CR₂)_(n)Het, SA and/or OA.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4-5-yl,2,1,3-benzoxadiazol-5-yl or dibenzofuranyl. The heterocyclic radicalsmay also be partially or fully hydrogenated. Irrespective of furthersubstitutions, Het can thus also denote, for example, 2,3-dihydro-2-,-3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2-or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-2-3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes a mono- or bicyclic saturated, unsaturated oraromatic heterocycle having 1 to 3 N, O and/or S atoms, which may beunsubstituted or mono- or disubstituted by Hal, A, NH₂ and/or ═O(carbonyl oxygen).

Het particularly preferably denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl tetrahydropyridazine, imidazolidinylbenzoxazolyl or benzo-2,1,3-thiadiazolyl, each of which is unsubstitutedor mono- or disubstituted by A and/or ═O (carbonyl oxygen).

Het¹ preferably denotes pyrrolidine, piperidine, piperazine ormorpholine, each of which is unsubstituted or mono- or disubstituted byA and/or ═O (carbonyl oxygen).

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

The indices have the following preferred meanings

-   m 1, 2, 3 or 4,-   n 0, 1, 2, 3 or 4,-   p 0, 1, 2, 3 or 4,-   q 0, 1 or 2.

Throughout the invention, all radicals which occur more than once, suchas, for example, R, may be identical or different, i.e. are independentof one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above,

Some preferred groups of compounds may be expressed by the followingsub-formulae Ia to Ip, which conform to the formula I and in which theradicals not designated in greater detail have the meaning indicated forthe formula I, but in which

-   in Ia R¹ denotes a bicyclic unsaturated or aromatic heterocycle    selected from the group

-   -   which may be unsubstituted or mono-, di- or trisubstituted by A,        Ar, SR, NR₂, Hal, NO₂, CN, (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, CONR₂,        OR⁵ and/or ═O (carbonyl oxygen);

-   in Ib R¹ denotes a bicyclic unsaturated or aromatic heterocycle    selected from the group

-    which may be unsubstituted or mono- or disubstituted by A, NR₂,    CONR₂, OR⁵ and/or ═O (carbonyl oxygen);-   in Ic R² denotes H or A;-   in Id denotes H;-   in Ie R⁴ denotes H;-   in If R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3 or    4 C atoms, in which 1-5H atoms may be replaced by F;-   in Ig K denotes CO or CH₂;-   in Ih F denotes COOCH₂, COOCH₂CH₂, SO₂CH₂CH₂, CONHCH₂, COCH₂O or    COCH₂CH₂;-   in Ii R denotes H or methyl;-   in Ij R denotes H;-   in Ik Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by    Hal, A, (CR₂)_(n)Het, SA and/or OA;-   in Il Het denotes a mono- or bicyclic saturated, unsaturated or    aromatic heterocycle having 1 to 3 N, O and/or S atoms, which may be    unsubstituted or mono- or disubstituted by Hal, A and/or ═O    (carbonyl oxygen);-   in Im Het denotes piperidinyl, piperazinyl, pyrrolidinyl,    morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,    triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl,    pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,    benzo-1,3-dioxolyl, indazolyl, tetrahydropyridazine, imidazolidinyl    benzoxazolyl or benzo-2,1,3-thiadiazolyl, each of which is    unsubstituted or mono- or disubstituted by A, NH₂, and/or ═O    (carbonyl oxygen);-   in In A denotes unbranched or branched alkyl having 1-10 C atoms, in    which 1-7H atoms may be replaced by F and/or Cl;-   in Io m denotes 1, 2, 3 or 4,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3 or 4,    -   q denotes 0, 1 or 2;-   in Ip R¹ denotes a bicyclic unsaturated or aromatic heterocycle    selected from the group

-    which may be unsubstituted or mono-, di- or trisubstituted by A,    Ar, SR, NR₂, Hal, NO₂, CN, (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, CONR₂, OR⁵    and/or ═O (carbonyl oxygen),    -   R² denotes H or A,    -   R³ denotes H,    -   R⁴ denotes H,    -   X denotes O, NR or CR₂,    -   Y denotes OR or NR₂,    -   R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3 or 4        C atoms, in which 1-5H atoms may be replaced by F,    -   K denotes CO or CH₂,    -   E denotes COOCH₂, COOCH₂CH₂, SO₂CH₂CH₂, CONHCH₂, COCH₂O or        COCH₂CH₂,    -   R denotes H or methyl,    -   W denotes Ar or Het,    -   G denotes CH or N,    -   Ar denotes phenyl, naphthyl or biphenyl, each of which is        unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by        Hal, A, (CR₂)_(n)Het, SA and/or OA,    -   Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,        furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,        triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl,        pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, indazolyl or benzo-2,1,3-thiadiazolyl, each        of which is unsubstituted or mono- or disubstituted by A and/or        ═O (carbonyl oxygen),    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by F and/or Cl,    -   m denotes 1, 2, 3 or 4,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3 or 4,    -   Hal denotes F, Cl, Br or I;        and pharmaceutically usable derivatives, salts, solvates,        tautomers and stereoisomers thereof, including mixtures thereof        in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting materials can, if desired, also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

In the compounds of the formula III, L preferably denotes Cl, Br, I or afree or reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline-earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali oralkaline-earth metals, preferably of potassium, sodium, calcium orcaesium, may also be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile, dichloromethane and/orDMF.

The starting compounds of the formulae II and Ill are generally known.If they are novel, however, they can be prepared by methods known perse. The starting materials, such as, for example, the compound 2 (seereaction scheme in Example 1), which are used for the preparation of thecompounds of the formula I are generally also commercially available.They can preferably be prepared analogously to the following schemes:

Preparation of a Piperazine Starting Material

Preparation of a Piperidine Starting Material:

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline-earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate; phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline-earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction,

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl and tea-butylchloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, for exampledimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides, forexample decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromideand iodide; and aryl(C₁-C₄)alkyl halides, for example benzyl chlorideand phenethyl bromide. Both water- and oil-soluble compounds accordingto the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline-earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which, comprises a compound of the formula Iin the form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or waterin-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, andfor anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof can also be administered in the form ofliposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or more usually in a series of part-doses (such as, for example,two, three, four, five or six) per day, so that the total daily dose isthe same. An effective amount of a salt or solvate or of aphysiologically functional derivative thereof can be determined as thefraction of the effective amount of the compound according to theinvention per se. It can be assumed that similar doses are suitable forthe treatment of other conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solnates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

The medicaments from Table 1 are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechlorethamine Thiotepa Streptozocin ChlorambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-FluorouracilFludarabine Floxuridine Pentostatin 2-Chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Idatrexate Roche)Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichi) Teniposideor Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma-Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-Ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-107088(Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone(Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin(Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin)Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin LosoxantroneDaunorubicin Bleomycin sulfate (Daunomycin) (Blenoxan) EpirubicinBleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin BRubidazone Mitomycin C Plicamycinp MEN-10755 (Menarini) PorfiromycinGPX-100 (Gem Cyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantrone(Novantrone) Antimitotic agents Paclitaxel SB 408075 Docetaxel(GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (CellVincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin(Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica)Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar)Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik)PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB (PrescientAuristatin PE (Teikoku NeuroPharma) hormone) Azaepothilon B (BMS) BMS247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug(OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga)CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitorsLetrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi)Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias)synthase ZD-9331 (BTG) CoFactor ™ (BioKeys) inhibitors DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine Thymectacin(NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl Arglabin(NuOncology Tipifarnib (Johnson & transferase Labs) Johnson) inhibitorsIonafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharma)BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) ZosuquidarTariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase inhibitors SAHA (Aton Pharma)(Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa) MetalloproteinaseNeovastat (Aeterna Laboratories) CMT-3 (CollaGenex) inhibitorsMarimastat (British Biotech) BMS-275291 (Celltech) RibonucleosideGallium maltolate (Titan) Tezacitabine (Aventis) reductase inhibitorsTriapin (Vion) Didox (Molecules for Health) TNF-alpha Virulizin (LorusTherapeutics) Revimid (Celgene) agonists/ CDC-394 (Celgene) antagonistsEndothelin-A receptor Atrasentan (Abbot) YM-598 (Yamanouchi) antagonistsZD-4054 (AstraZeneca) Retinoic acid receptor Fenretinide (Johnson &Alitretinoin (Ligand) agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (Gem- Vax) Hormonal and OestrogensPrednisone antihormonal Conjugated oestrogens Methylprednisolone agentsEthynyloestradiol Prednisolone Chlorotrianisene AminoglutethimideIdenestrol Leuprolide Hydroxyprogesterone Goserelin caproate LeuporelinMedroxyprogesterone Bicalutamide Testosterone Flutamide Testosteronepropionate Octreotide Fluoxymesterone Nilutamide MethyltestosteroneMitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol(Entre Tamoxifen Med) Toremofin Arzoxifen (Eli Lilly) DexamethasonePhotodynamic Talaporfin (Light Sciences) Pd-bacteriopheophorbide agentsTheralux (Theratechnologies) (Yeda) Motexafin gadolinium Lutetiumtexaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinaseImatinib (Novartis) Kahalide F (PharmaMar) inhibitors LeflunomideCEP-701 (Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839(AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis)Science) Phenoxodiol O Canertjnib (Pfizer) Trastuzumab (Genentech)Squalamine (Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab(Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca)2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib(Novartis) ABX-EGF (Abgenix) PKI166 (Novartis) IMC-1C11 (ImClone) GW2016(GlaxoSmith- Kline) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor,Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon)CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic)inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaBGlycoGenesys) inhibitor, Active Biotech) G17DT immunogen (gastrinSeocalcitol (vitamin D inhibitor, Aphton) receptor agonist, Leo)Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, PI-88 (heparanase inhibitor, TransMolecular) Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine antagonist, ILEXOncology) YM BioSciences) Minodronic acid Histamine (histamine H2(osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin(IMPDH inhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai)Cilengitide (integrin antagonist, Aplidin (PPT inhibitor, Merck KGaA)PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody,Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33inhibitor, Wyeth) antibody, Wyeth Ayerst) Exisulind (PDE-V inhibitor,PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug,Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activatorinhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant,TransMID-107 ™ ProMetic LifeSciences) (immunotoxin, KS Bortezomib(proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172(T-cell stimulant, promoter, Procyon) SR Pharma) Doranidazole (apoptosisTLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik)CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, PointTherapeutics) Trans-retinoic acid Midostaurin (PKC inhibitor,(differentiator, NIH) Novartis) MX6 (apoptosis promoter, Bryostatin-1(PKC stimuant, MAXIA) GPC Biotech) Apomine (apoptosis CDA-II (apoptosispromoter, promoter, ILEX Oncology) Everlife) Urocidin (apoptosis SDX-101(apoptosis promoter, promoter, Bioniche) Salmedix) Ro-31-7453 (apoptosisCeflatonin (apoptosis promoter, promoter, La Roche) moter, ChemGenex)Brostallicin (apoptosis promoter, Pharmacia) Alkylating agentsCyclophosphamide Lomustine Busulfan Procarbazine Ifosfamide AltretamineMelphalan Estramustine phosphate Hexamethylmelamine MechlorethamineThiotepa Streptozocin Chlorambucil Temozolomide Dacarbazine SemustineCarmustine Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473(AnorMED) Spiroplatin Lobaplatin (Aetema) CarboxyphthalatoplatinumSatraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 Iproplatin(Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access)Antimetabolites Azacytidine Tomudex Gemcitabine TrimetrexateCapecitabine Deoxycoformycin 5-Fluorouracil Fludarabine FloxuridinePentostatin 2-Chlorodesoxyadenosine Raltitrexed 6-MercaptopurineHydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine(Bioenvision) 2-Fluorodesoxycytidine Irofulven (MGI Pharrna)Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taiho)Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors EpirubicinExatecan mesylate Etoposide (Daiichi) Teniposide or Quinamed (ChemGenex)mitoxantrone Gimatecan (Sigma-Tau) Irinotecan (CPT-11) Diflomotecan(Beaufour- 7-Ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho)Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-107088 (Merck & Co)(TopoTarget) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602(Chong Kun Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko)BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafideantibiotics D) Azonafide Doxorubicin (Adriamycin) AnthrapyrazoleDeoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin Bleomycinsulfate (Daunomycin) (Blenoxan) Epirubicin Bleomycinic acid TherarubicinBleomycin A Idarubicin Bleomycin B Rubidazone Mitomycin C PlicamycinpMEN-10755 (Menarini) Porfiromycin GPX-100 (Gem Cyanomorpholinodoxo-Pharmaceuticals) rubicin Mitoxantrone (Novantrone) Antimitotic agentsPaclitaxel SB 408075 Docetaxel (GlaxoSmithKline) Colchicine E7010(Abbott) Vinblastine PG-TXL (Cell Vincristine Therapeutics) VinorelbineIDN 5109 (Bayer) Vindesine A 105972 (Abbott) Dolastatin 10 (NCI) A204197 (Abbott) Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner-D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF)Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD258 (Aventis) (PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca)T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992(Asahi) Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre)AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) hormone)Azaepothilon B (BMS) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476(BMS) CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH)Taxoprexin (Protarga) CA-4 (OXiGENE) Aromatase AminoglutethimideExemestan inhibitors Letrozole Atamestan (BioMedicines) AnastrazoleYM-511 (Yamanouchi) Formestan Thymidylate Pemetrexed (Eli Lilly)Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor ™ (BioKeys)inhibitors DNA antagonists Trabectedin (PharmaMar) Mafosfamide (BaxterGlufosfamide (Baxter International) International) Apaziquone (SpectrumAlbumin + 32P (Isotope Pharmaceuticals) Solutions) O6-benzylguanineThymectacin (NewBiotics) (Paligent) Edotreotid (Novartis) FarnesylArglabin (NuOncology Tipifarnib (Johnson & transferase Labs) Johnson)inhibitors Ionafarnib (Schering- Perillyl alcohol (DOR Plough)BioPharma) BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma)Zosuquidar Tariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209(Schering AG) Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline(Pfizer) Pivaloyloxymethyl butyrate transferase inhibitors SAHA (AtonPharma) (Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna Laboratories) CMT-3 (CollaGenex)inhibitors Marimastat (British Biotech) BMS-275291 (Celltech)Ribonucleoside Gallium maltolate (Titan) Tezacitabine (Aventis)reductase inhibitors Triapin (Vion) Didox (Molecules for Health)TNF-alpha Virulizin (Lorus Therapeutics) Revimid (Celgene) agonists/CDC-394 (Celgene) antagonists Endothelin-A receptor Atrasentan (Abbot)YM-598 (Yamanouchi) antagonists ZD-4054 (AstraZeneca) Retinoic acidreceptor Fenretinide (Johnson & Alitretinoin (Ligand) agonists Johnson)LGD-1550 (Ligand) Immunomodulators Interferon Dexosome therapy (Anosys)Oncophage (Antigenics) Pentrix (Australian Cancer GMK (Progenics)Technology) Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancervaccine (Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2(Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics)Synchrovax vaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera(Vasogen) Melanoma vaccine (CTL Immuno) p21-RAS vaccine (Gem- Vax)Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogensMethylprednisolone agents Ethynyloestradiol PrednisoloneChlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone Goserelin caproate Leuporelin MedroxyprogesteroneBicalutamide Testosterone Flutamide Testosterone propionate OctreotideFluoxymesterone Nilutamide Methyltestosterone Mitotan DiethylstilbestrolP-04 (Novogen) Megestrol 2-Methoxyoestradiol (Entre Tamoxifen Med)Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin(Light Sciences) Pd-bacteriopheophorbide agents Theralux(Theratechnologies) (Yeda) Motexafin gadolinium Lutetium texaphyrin(Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib(Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide CEP-701(Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca)MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science)Phenoxodiol O Canertjnib (Pfizer) Trastuzumab (Genentech) Squalamine(Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668(Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech)ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX-EGF(Abgenix) PKI166 (Novartis) IMC-1C11 (ImClone) GW2016 (GlaxoSmith-Kline) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agents SR-27897 (CCK-Ainhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo) BioCryst)Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist, Ribapharm)stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNAsynthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor,Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon)CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic)inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaBGlycoGenesys) inhibitor, Active Biotech) G17DT immunogen (gastrinSeocalcitol (vitamin D inhibitor, Aphton) receptor agonist, Leo)Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, PI-88 (heparanase inhibitor, TransMolecular) Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine antagonist, ILEXOncology) YM BioSciences) Minodronic acid Histamine (histamine H2(osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin(IMPDH inhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai)Cilengitide (integrin antagonist, Aplidin (PPT inhibitor, Merck KGaA)PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody,Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33inhibitor, Wyeth) antibody, Wyeth Ayerst) Exisulind (PDE-V inhibitor,PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug,Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activatorinhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant,TransMID-107 ™ ProMetic LifeSciences) (immunotoxin, KS Bortezomib(proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172(T-cell stimulant, promoter, Procyon) SR Pharma) Doranidazole (apoptosisTLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik)CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, PointTherapeutics) Trans-retinoic acid Midostaurin (PKC inhibitor,(differentiator, NIH) Novartis) MX6 (apoptosis promoter, Bryostatin-1(PKC stimulant, MAXIA) GPC Biotech) Apomine (apoptosis CDA-II (apoptosispromoter, promoter, ILEX Oncology) Everlife) Urocidin (apoptosis SDX-101(apoptosis promoter, promoter, Bioniche) Salmedix) Ro-31-7453 (apoptosisCeflatonin (apoptosis promoter, promoter, La Roche) ChemGenex)Brostallicin (apoptosis promoter, Pharmacia)

The compounds of the formula I are preferably combined with the withknown anti-cancer agents:

These known anti-cancer agents include the following: oestrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic agents, antiproliferative agents, prenyl-protein transferaseinhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors and other angiogenesis inhibitors. Thepresent compounds are particularly suitable for administration at thesame time as radiotherapy. The synergistic effects of inhibition of VEGFin combination with radiotherapy have been described in the art (see WO00/61186). “Oestrogen receptor modulators” refers to compounds whichinterfere with or inhibit the binding of oestrogen to the receptor,regardless of mechanism. Examples of oestrogen receptor modulatorsinclude, but are not limited to, tamoxifen, raloxifene, idoxifene,LY353381, LY 117081, toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.“Androgen receptor modulators” refers to compounds which interfere withor inhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere withor inhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenyl retinamide.

“Cytotoxic agents” refers to compounds which result in cell deathprimarily through direct action on the cellular function or inhibit orinterfere with cell myosis, including alkylating agents, tumour necrosisfactors, intercalators, microtubulin inhibitors and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosylate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cisaminedichloro(2-methylpyridine)platinum, benzylguanine, glufosfamide,GPX100,(trans,trans,trans)bis-mu-(hexane-1,6-diamine)mu-[diamineplatinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplastone,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycamptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exobenzylidenechartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxyetoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

“Antiproliferative agents” include antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 andanti-metabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-mannoheptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also include monoclonal antibodies to growth factors other thanthose listed under “angiogenesis inhibitors”, such as trastuzumab, andtumour suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

Particular preference is given to the use of the compound according tothe invention for the treatment and prophylaxis of tumour diseases.

The tumour is preferably selected from the group of tumours of thesquamous epithelium, of the bladder, of the stomach, of the kidneys, ofhead and neck, of the esophagus, of the cervix, of the thyroid, of theintestine, of the liver, of the brain, of the prostate, of theurogenital tract, of the lymphatic system, of the stomach, of the larynxand/or of the lung.

The tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

In another aspect, the invention encompasses a for the treatment of apatient who has a neoplasm, such as a cancer, by administration of acompound of the formula (I) in combination with an antiproliferativeagent. Suitable antiproliferative agents encompass those provided inTable 1.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: if necessary, water is added,the pH is adjusted, if necessary, to values between 2 and 10, dependingon the constitution of the end product, the mixture is extracted withethyl acetate or dichloromethane, the phases are separated, the organicphase is dried over sodium sulfate and evaporated, and the product ispurified by chromatography on silica gel and/or by crystallisation. Rfvalues on silica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺

LC/MS Method:

-   Solvent A: water+0.1% of TFA-   Solvent B: acetonitrile+0.1% of TFA-   Flow: 2.4 ml/min-   Gradient: 0.0 min 4% of B    -   2.6 min 100% of B-   Column: Chromolith® Speed ROD RP-18e 50-4, 6 mm

HPLC Method:

-   Solvent A: water+0.1% of TFA-   Solvent B: acetonitrile 0.08% of TFA-   Flow: 1.5 ml/min-   Gradient: 0.0 min 20% of B    -   6.0 min 100% of B    -   7.0 min 100% of B    -   8.0 min 20% of B    -   9.0 min 20% of B-   Column: Chromolith® RP18e 100-4, 6 mm

EXAMPLE 1

The synthesis of 4-chlorobenzyl4-[4-(1H-benzotriazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate(“A1”) is carried out analogously to the following scheme

1.1 5-Aminobenzotriazole 1 (0.69 g, 5.15 mmol) and compound 2 (1.61 g,5.15 mmol) are initially introduced in DMF (15 ml),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.99 g,5.15 mmol) and 1-hydroxybenzotriazole (0.70 g, 5.15 mmol) are added atroom temperature (RT), and the mixture is stirred at RT for 15 h. Thereaction solution is poured into water, and the precipitate formed isfiltered off. This is washed with water and dried (vacuum dryingcabinet). The colourless product obtained is reacted without furtherpurification (colourless solid 3, 1.45 g, 3.38 mmol, 66%).

1.2 Compound 3 (1.14 g, 2.66 mmol) is taken up in 6N HCl in 2-propanol(45 ml) and stirred further at RT for 1 h. The reaction mixture isevaporated to dryness, and the residue is triturated with ethylacetate/diethyl ether. The precipitate is filtered off and dried, givingcompound 4 (0.89 g, 2.45 mmol, 92%).

1.3 4-Chlorobenzyl alcohol (32.2 mg, 0.23 mmol) is dissolved in DMF (3ml), 1,1′-carbonyldiimidazole (36.6 mg, 0.23 mmol) is added, and themixture is stirred further at RT for 2 h. Compound 4 (60.0 mg, 0.19mmol), dissolved in DMF (1 ml), is added to this mixture at RT. Stirringis continued at RT for 18 h. The reaction mixture is poured into water(20 ml), and the resultant precipitate is filtered off. This is washedwith water and dried (vacuum drying cabinet), giving “A1” (75.2 mg, 0.15mmol, 66%); [M+H]⁺499; HPLC 4.91

EXAMPLE 2 Preparation of 3,5-dichlorobenzyl4-{5-[(1H-benzotriazol-5-ylamino)methyl]-4-methylthiazol-2-yl}piperidine-1-carboxylate(13)

The reduced analogue compounds can be synthesised as follows

5-Aminobenzotriazole 1 (162 mg, 1.12 mmol) and commercially availabletert-butyl4-(5-formyl-4-methyl-1,3-thiazol-2-yl)piperidine-1-carboxylate 11 (250mg, 0.81 mmol) is initially introduced in DCM/THF (2:1, 6 ml), aceticacid (46 μl, 0.81 mmol) is added, and the mixture is stirred at RT for 3h. Sodium triacetoxyborohydride (0.31 g, 1.45 mmol) is subsequentlyadded, and stirring is continued overnight. Saturated NaHCO₃ solution isadded to the batch, which is extracted 2× with ethyl acetate, dried overNa₂SO₄, filtered and evaporated to dryness. The colourless solidobtained is reacted further without further purification.

Compound 13 is obtained therefrom analogously to b. and c. in Example 1.

The following compounds are obtained analogously to Example 1 or Example2

HPLC Compound ESI (RT in min) No. Name and/or structure [M + H]⁺ method“A2” 4-Chlorobenzyl 4-[4-(2-oxo-2,3-dihydro-benz- 515 5.04oxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate

¹H—NMR (DMSO-d₆): δ [ppm] = 3.58 (s(b), 8H), 5.13 (s, 2H), 7.07 (d, 1H),7.41- 7.48 (m, 4H), 7.54 (dd, 1H), 7.61 (s, 1H), 7.82 (d, 1H), 9.84 (s,1H), 11.56 (s, 1H). “A3” 4-Trifluoromethylsulfanylbenzyl 4-[4-(1H-benzo-565 triazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate

“A4” 4-Trifluoromethoxybenzyl 4-[4-(1H-benzotriazol- 5495-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate

¹H—NMR (DMSO-d₆): δ [ppm] = 3.61 (bs, 8H), 5.16 (s, 2H), 7 38 (d, 2H),7.52 (d, 2H), 7.65 (s, 1H), 7.72 (d, 1H), 7.92 (d, 1H), 8.45 (s, 1H),9.53 (s, 1H), 15.45 (bs, 1H). “A5” 4-Trifluoromethylbenzyl4-[4-(1H-benzotriazol-5- 533ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate ¹H—NMR (DMSO-d₆): δ[ppm] = 3.62 (bs, 8H), 5.22 (s, 2H), 7.62 (d, 2H), 7.67 (s, 1H), 7.71(dd, 1H), 7.75 (d, 2H), 7.91 (d, 1H), 8.46 (s, 1H), 9.54 (s, 1H), 15.45(bs, 1H). “A6” 4-Fluorobenzyl 4-[4-(1H-benzotriazol-5-yl- 483carbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A7” 4-Methylbenzyl4-[4-(1H-benzotriazol-5-yl- 479carbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A8” 4-Ethylbenzyl4-[4-(1H-benzotriazol-5-yl- 493carbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A9” 3,5-Dichlorobenzyl4-[4-(1H-benzotriazol-5-yl- 533carbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A10”4-Trifluoromethylsulfanylbenzyl 4-[4-(2-oxo-2,3- 581dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate“A11” 4-Trifluoromethoxybenzyl 4-[4-(2-oxo-2,3- 565dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate¹H—NMR (DMSO-d₆): δ [ppm] = 3.58 (bs, 8H), 5.16 (s, 2H), 7.06 (d, 1H),7.37 (d, 2H), 7.52 (m, 3H), 7.60 (s, 1H), 7.83 (d, 1H), 9.83 (s, 1H),11.50 (bs, 1H). “A12” 4-Trifluoromethylbenzyl 4-[4-(2-oxo-2,3-dihydro-549 benzoxazol-6-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate“A13” 4-Fluorobenzyl 4-[4-(2-oxo-2,3-dihydrobenz- 499oxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate “A14”4-Methylbenzyl 4-[4-(2-oxo-2,3-dihydrobenz- 495oxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate “A15”4-Ethylbenzyl 4-[4-(2-oxo-2,3-dihydrobenz- 509oxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate “A16”3,5-Dichlorobenzyl 4-[4-(2-oxo-2,3-dihydro- 549benzoxazol-6-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate “A17”4-tert-Butylbenzyl 4-[4-(1H-benzotriazol-5-yl- 521carbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A18” 4-tert-Butylbenzyl4-[4-(2-oxo-2,3-dihydro- 537 benzoxazol-6-ylcarbamoyl)thiazol-2-yl]-piperazine-1-carboxylate “A19” 4-Phenylbenzyl 4-[4-(2-oxo-2,3-dihydro-557 benzoxazol-6-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate“A20” 4-Morpholin-4-ylmethylbenzyl 4-[4-(2-oxo-2,3- 580dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate

“A21” 4-Trifluoromethylsulfanylbenzyl 4-[4-(1H-indazol- 5645-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate

“A22” 4-Trifluoromethylsulfanylbenzyl 4-[4-(1H-indol-5- 563ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A23” 4-Trifluoromethylsulfanylbenzyl 4-[4- 581(benzothiazol-6-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate

“A24” 4-Trifluoromethylsulfanylbenzyl 4-[4-(benzo- 5821,2,5-thiadiazol-5-ylcarbamoyl)thiazol-2-yl]- piperazine-1-carboxylate

“A25” 4-Trifluoromethylsulfanylbenzyl 4-[4-(2- 632trifluoromethyl-1H-benzimidazol-5-ylcarbamoyl)-thiazol-2-yl]piperazine-1-carboxylate

“A26” N-(1H-Benzotriazol-5-yl)-2-{4-[2-(4-chloro- 499phenoxy)acetyl]piperazin-1-yl}thiazole-4- carboxamide

“A27” N-(1H-Benzotriazol-5-yl)-2-{4-[2-(4-chloro- 498phenylamino)acetyl]piperazin-1-yl}thiazole-4- carboxamide

“A28” 4-Chlorobenzyl 4-[4-(2-oxo-2,3-dihydro- 514 5.12benzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine- 1-carboxylate

“A29” 4-Chlorobenzyl 4-[4-(1H-benzotriazol-5-yl- 498 4.91carbamoyl)thiazol-2-yl]piperidine-1-carboxylate

“A30” 4-Isopropylbenzyl 4-[4-(2-oxo-2,3-dihydrobenz- 522 5.47oxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine-1- carboxylate “A31”3,4-Dimethylbenzyl 4-[4-(2-oxo-2,3-dihydrobenz- 508 5.17oxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine-1- carboxylate “A32”3,4-Dimethylbenzyl 4-[4-(1H-benzotriazol-5-yl- 492 4.99carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A33” 2,4-Dichlorobenzyl4-[4-(2-oxo-2,3-dihydrobenz- 548 5.49oxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine-1- carboxylate “A34”2,4-Dichlorobenzyl 4-[4-(1H-benzotriazol-5-yl- 532 5.33carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A35” 3,5-Dichlorobenzyl4-[4-(2-oxo-2,3-dihydro- 548 5.6benzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine- 1-carboxylate “A36”4-Trifluoromethylsulfanylbenzyl 4-[4-(2-oxo-2,3- 580 5.31dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]- piperidine-1-carboxylate¹H—NMR (DMSO-d₆): δ [ppm] = 1.68-1.78 (m, 2H), 2.14 (d, 2H), 3.06 (s(b),2H), 3.32-3.38 (m, 1H), 4.15 (d, 2H), 5.19 (s, 2H), 7.07 (d, 1H), 7.54(d, 2H), 7.58 (dd, 1H), 7.75 (d, 2H), 7.84 (d, 1H), 8.33 (s, 1H), 10.10(s, 1H), 11.57 (s, 1H). “A37” 4-Trifluoromethylbenzyl4-[4-(2-oxo-2,3-dihydro- 548 5.25benzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine- 1-carboxylate “A38”4-Chlorobenzyl 4-{4-[(1H-benzotriazol-5-yl- 484amino)methyl]thiazol-2-yl}piperidine-1- carboxylate

“A39” 4-Chlorobenzyl 4-{5-[(1H-benzotriazol-5-yl- 498amino)methyl]-4-methylthiazol-2-yl}piperidine-1- carboxylate

“A40” N-(4-Trifluoromethoxybenzyl)-4-[4-(1H-benzo- 547triazol-5-ylcarbamoyl)thiazol-2-yl]piperidine-1- carboxamide

“A41” N-(1H-Benzotriazol-5-yl)-2-{1-[2-(4-chloro- 498phenoxy)acetyl]piperidin-4-yl}thiazole-4- carboxamide

“A42” N-(1H-Benzotriazol-5-yl)-2-{1-[3-(4-trifluoro- 530methylphenyl)propionyl]piperidin-4-yl}thiazole-4- carboxamide

¹H—NMR (DMSO-d₆): δ [ppm] = 1.56-1.68 (m, 2H), 2.07-2.16 (m, 2H), 2.66-2.80 (m, 3H), 2.94 (t, 2H), 3.17 (t, 1H), 3.36-3.42 (m, 1H), 4.00 (d,1H), 4.51 (d, 1H), 7.50 (d, 2H), 7.63 (d, 2H), 7.75 (d, 1H), 7.93 (d,1H), 8.38 (s, 1H), 8.48 (s, 1H), 10.29 (s, 1H), 15.57 (s, 1H). “A43”N-(1H-Benzotriazol-5-yl)-2-[1-(2-phenylethyl- 498sulfonyl)piperidin-4-yl]thiazole-4-carboxamide

“A44” 4-Chlorobenzyl 4-[4-(2-trifluoromethyl-1H- 565benzimidazol-5-ylcarbamoyl)thiazol-2-yl]- piperidine-1-carboxylate “A45”4-Chlorobenzyl 4-[4-(1H-indazol-5-ylcarbamoyl)- 497thiazol-2-yl]piperidine-1-carboxylate “A46”N-(2-Trifluoromethyl-1H-benzimidazol-5-yl)-2-{1- 597[3-(4-trifluoromethylphenyl)propionyl]piperidin-4-yl}thiazole-4-carboxamide

“A47” N-(2-Oxo-2,3-dihydrobenzoxazol-6-yl)-2-{1-[3-(4- 546trifluoromethylphenyl)propionyl]piperidin-4-yl}- thiazole-4-carboxamide

¹H—NMR (DMSO-d₆): δ [ppm] = 1.53-1.67 (m, 2H), 2.05-2.15 (m, 2H), 2.67-2.80 (m, 3H), 2.93 (t, 2H), 3.16 (t, 1H), 3.32-3.40 (m, 1H), 3.99 (d,1H), 4.49 (d, 1H), 7.07 (d, 1H), 7.50 (d, 2H), 7.56 (dd, 1H), 7.63 (d,2H), 7.83 (s, 1H), 8.31 (s, 1H), 10.08 (s, 1H), 11.56 (s, 1H). “A48”1-(4-{4-[(1H-Benzotriazol-5-ylamino)methyl]- 516thiazol-2-yl}piperidin-1-yl)-3-(4-trifluoromethyl- phenyl)propan-1-one

“A49” 3,5-Dichlorobenzyl 4-{4-[(1H-benzotriazol-5-yl- 518amino)methyl]thiazol-2-yl}piperidine-1- carboxylate

“A50” 4-Trifluoromethylsulfanylbenzyl 4-{5-[(1H- 564benzotriazol-5-ylamino)methyl]-4-methylthiazol-2-yl}piperidine-1-carboxylate

“A51” 3,5-Dichlorobenzyl 4-[4-(benzothiazol-6-yl- 548carbamoyl)thiazol-2-yl]piperidine-1-carboxylate

“A52” N-(Benzothiazol-6-yl)-2-{1-[3-(4-trifluoromethyl- 546phenyl)propionyl]piperidin-4-yl}thiazole-4- carboxamide

“A53” N-(2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2- 545{1-[3-(4-trifluoromethylphenyl)propionyl]piperidin-4-yl}thiazole-4-carboxamide

“A54” 4-Chlorobenzyl 4-[4-(2-oxo-2,3-dihydro-1H- 513benzimidazol-5-ylcarbamoyl)thiazol-2-yl]- piperidine-1-carboxylate

“A55” 3,5-Dichlorobenzyl 4-[4-(1H-benzimidazol-5-yl- 531carbamoyl)thiazol-2-yl]piperidine-1-carboxylate

“A56” 3,5-Dichlorobenzyl 4-[5-(1H-benzotriazol-5-yl- 546carbamoyl)-4-methylthiazol-2-yl]piperidine-1- carboxylate

3,5-Dichlorobenzyl 4-[5-(1H-benzotriazol-5-yl-carbamoyl)-4-methylthiazol-2-yl]piperidine-1- carboxylate

The following compounds can be prepared using methods known to theperson skilled in the art. They are preferably prepared by the syntheticmethods from Example 1 or 2 of the above-mentioned compounds:

HPLC Compound ESI (RT in min) No. Name and/or structure [M + H]⁺ method“B1” 

512 3.60 4-Chlorobenzyl 4-[4-(3-amino-1H-indazol-6-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B2” 

546 4.21 3,5-Dichlorobenzyl 4-[4-(3-amino-1H-indazol-6-ylcarbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B3” 

489 3.52 4-Chlorobenzyl 4-[4-(3-imidazol-1-ylpropyl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B4” 

567 4.69 4-Chlorobenzyl 4-{4-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenylcarbamoyl]-thiazol-2-yl}piperidine-1-carboxylate “B5” 

535 4.00 4-Chlorobenzyl 4-{4-[3-(4-methyl-2,5-dioxo-imidazolidin-4-yl)propylcarbamoyl]thiazol-2-yl}-piperidine-1-carboxylate “B6” 

475 3.57 4-Chlorobenzyl 4-[4-(2-imidazol-1-ylethyl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B7” 

544 3.71 N-(3-Amino-1H-indazol-5-yl)-2-{1-[3-(4-trifluoro-methylphenyl)propionyl]piperidin-4-yl}thiazole-4- carboxamide “B8” 

540 3.84 4-Chlorobenzyl 4-{4-[2-(2-amino-1H-benz-imidazol-5-yl)ethylcarbamoyl]thiazol-2-yl}- piperidine-1-carboxylate“B9” 

512 3.92 4-Chlorobenzyl 4-[4-(3-amino-1H-indazol-5-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B10”

509 3.89 3,5-Dichlorobenzyl 4-{4-[2-(1H-imidazol-4-yl)-ethylcarbamoyl]thiazol-2-yl}piperidine-1- carboxylate “B11”

503 3.15 4-Chlorobenzyl 4-{4-[3-(3-oxo-3H-pyrazol-4-yl)-propylcarbamoyl]thiazol-2-yl}piperidine-1- carboxylate “B12”

509 3.87 3,5-Dichlorobenzyl 4-[4-(2-imidazol-1-ylethyl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B13”

471 4.99 4-Chlorobenzyl 4-[4-(2-oxo-2,3-dihydrobenz-oxazol-6-yl)thiazol-2-yl]piperidine-1-carboxylate “B14”

483 3.89 N-(4-Chlorophenyl)-4-[4-(1H-benzotriazol-5-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxamide “B15”

560 4.59 3,5-Dichlorobenzyl 4-{4-[(1H-benzotriazol-5-yl-carbamoyl)methyl]-5-methylthiazol-2-yl}- piperidine-1-carboxylate

EXAMPLE A Autotaxin Test

Test Description

The autotaxin activity is measured indirectly using Amplex Red reagent.Amplex Red is measured here as fluorogenic indicator for the H₂O₂formed. In detail, autotaxin converts the substratelysophosphatidylcholine (LPC) into phosphocholine and lysophosphatidylicacid (LPA). After this reaction, the phosphocholine is reacted withalkaline phosphatase to give inorganic phosphate and choline. In thenext step, choline is oxidised by choline oxidase to give betaine, withformation of H₂O₂. H₂O₂ reacts with Amplex Red reagent in the presenceof peroxidase (horseradish peroxidase) in a 1:1 stoichiometry and formsthe highly fluorescent resorufine. The fluorescence is measured in areaction-dependent kinetic mode in order that fluorescent signals frompossible other fluorescent substances which are not involved in thereaction can be corrected out.

Test Procedure

1.5 μl of a standard solution or of the test substances (substances withthe name A(n)) in individual concentrations dissolved in 20 mM Hepes pH7.2 with a maximum of 7.7% of DMSO are pre-incubated together with 10 μl(16 ng) of highly purified recombinant autotaxin in a black microtitreplate provided with 384 wells at 22° C. for 30 min. The reaction is theninitiated by addition of 5 μl of L-a-lysophosphatidylcholine (LPC),where the final concentration of LPC is 75 μM. The mixture is incubatedat 37° C. for 90 min. After the incubation, Amplex Red reagent,peroxidase (horseradish peroxidase) and choline oxidase is added, andthe fluorescence is immediately measured at 612 nm with excitation of485 nm in a “Tecan Ultra multimode” reader. The activity of autotaxin iscalculated indirectly via detection of the H₂O₂ formed.

Material:

-   Microtitre plate: PS microplate, 384 wells, small volume, black    Corning, Cat#3677-   Protein: recombinant autotaxin (Baculovirale Hi5 Expression)-   Substrate: L-a-lysophosphatidylcholine (chicken egg)); Avanti Polar    Lipids # 830071P-   Standard: C14 LPA, Avanti Polar Lipids, Cat# 857120P-   Detection reagent: Amplex Red reagent; Invitrogen # A12222;    dissolved in 1.923 ml of DMSO peroxidase type VI-A (horseradish)    from Sigma # P6782; dissolved in 7.45 ml of test buffer, choline    oxidase; Sigma # C5896; dissolved in 2.47 ml of test buffer-   Detection reagent mix: 1:100 dilution of Amplex Red reagent in test    buffer-   Test buffer: 200 mM Tris HCl, Merck, Cat # 1.08219, pH 7.9, 0.1% of    BSA, lipid-free, Roche Cat#775835

The following examples relate to medicaments:

EXAMPLE B Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 31 of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE C Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE D Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE E Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE F Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE G Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE H Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE I Ampoules

A solution of 1 kg of active ingredient of the formula I in 601 ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. A compound of formula I

in which R¹ denotes a fused bicyclic unsaturated or aromatic heterocyclehaving 1 to 4 N, 0 and/or S atoms, which is unsubstituted or mono-, di-or trisubstituted by A, Ar, SR, NR₂, Hal, NO₂, CN,(CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, CONR₂, OR⁵ and/or ═O (carbonyl oxygen), R²,R³ each, independently of one another, denote H, A, Ar, OR, SR, NR₂,Hal, NO₂, CN or (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, R⁴ denotes H, Hal, A, OR,NR₂ or (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, X denotes O, NR or CR₂, Y denotes ORor NR₂, R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3, 4,5 or 6 C atoms, in which 1-7 H atoms may be replaced by F and/or Cl, Kdenotes C═O, CR₂CO or CR₂, E denotes COOCH₂, CONHCH₂ or COCH₂O, Rdenotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 Catoms, W denotes Ar or Het, G denotes CH or N, Ar denotes phenyl,naphthyl or biphenyl, each of which is unsubstituted or mono-, di-,tri-, tetra- or pentasubstituted by Hal, A, (CR₂)_(n)OR, (CR₂)NR₂, SR,NO₂, CN, COOR, CONR₂, NRCOA, NRSO₂A, SO₂NR₂, S(O)_(q)A, CO-Het,(CR₂)_(n)Het, O(CR₂)_(n)-NR₂, O(CR₂)_(n)Het, NHCOOA, NHCONR₂,NHCOO(CR₂)_(n)NR₂, NHCOO(CR₂)_(n)Het, NHCONH(CR₂)_(n)NR₂,NHCONH(CR₂)_(n)Het, OCONH(CR₂)_(n)NR₂, OCONH(CR₂)_(n)Het,CONR(CR₂)_(n)NR₂, CONR(CR₂)_(n)Het and/or COA, Het denotes a mono-, bi-or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to4 N, O and/or S atoms, which is unsubstituted or mono-, di- ortrisubstituted by Hal, A, (CR₂)_(n)OR, (CR₂)_(n)NR₂, SR, NO₂, CN, COOR,CONR₂, NRCOA, NRSO₂A, SO₂NR₂, S(O)_(q)A, CO-Het¹, (CR₂)_(n)Het¹,O(CR₂)_(n)NR₂, O(CR₂)_(n)Het¹, NHCOOA, NHCONR₂, NHCOO(CR₂)_(n)NR₂,NHCOO(CR₂)_(n)Het¹, NHCONH(CR₂)_(n)NR₂, NHCONH(CR₂)_(n)Het¹,OCONH(CR₂)_(n)NR₂, OCONH(CR₂)_(n)Het¹, CO-Het¹, CHO, COA, ═S, ═NH, ═NAand/or ═O (carbonyl oxygen), Het¹ denotes a monocyclic saturatedheterocycle having 1 to 2 N and/or O atoms, which may be mono- ordisubstituted by A, OA, OH, Hal and/or ═O (carbonyl oxygen), A denotesunbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atomsmay be replaced by OR, CN, NR₂, F and/or Cl and/or in which one or twonon-adjacent CH₂ groups may be replaced by O, NH, S, SO, SO₂ and/or byCH═CH groups, or cyclic alkyl having 3-7 C atoms, m denotes 1, n denotes1, p denotes 1, q denotes 0, 1 or 2, and Hal denotes F, Cl, Br or I, ora pharmaceutically acceptable salt or tautomer thereof.
 2. A compoundaccording to claim 1, in which R¹ denotes a bicyclic unsaturated oraromatic heterocycle, which is one of the following groups

which is unsubstituted or mono-, di- or trisubstituted by A, Ar, SR,NR₂, Hal, NO₂, CN, (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, CONR₂, OR⁵ and/or ═O(carbonyl oxygen), or a pharmaceutically acceptable salt or tautomerthereof.
 3. A compound according to claim 1, in which R¹ denotes abicyclic unsaturated or aromatic heterocycle, which is one of thefollowing groups

which is unsubstituted or mono- or disubstituted by A, NR₂, CONR₂, OR⁵and/or ═O (carbonyl oxygen), or a pharmaceutically acceptable salt ortautomer thereof.
 4. A compound according to claim 1, in which R²denotes H or A, or a pharmaceutically acceptable salt or tautomerthereof.
 5. A compound according to claim 1, in which R³ denotes H, or apharmaceutically acceptable salt or tautomer thereof.
 6. A compoundaccording to claim 1, in which R⁴ denotes H, or a pharmaceuticallyacceptable salt or tautomer thereof.
 7. A compound according to claim 1,in which R⁵ denotes H or unbranched or branched alkyl having 1, 2, 3 or4 C atoms, in which 1-5 H atoms may be replaced by F, or apharmaceutically acceptable salt or tautomer thereof.
 8. A compoundaccording to claim 1, in which K denotes CO or CH₂, or apharmaceutically acceptable salt or tautomer thereof.
 9. A compoundaccording to claim 1, in which R denotes H or methyl, or apharmaceutically acceptable salt or tautomer thereof.
 10. A compoundaccording to claim 1, in which R denotes H, or a pharmaceuticallyacceptable salt or tautomer thereof.
 11. A compound according to claim1, in which Ar denotes phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A,(CR₂)_(n) Het, SA and/or OA, or a pharmaceutically acceptable salt ortautomer thereof.
 12. A compound according to claim 1, in which Hetdenotes a mono- or bicyclic saturated, unsaturated or aromaticheterocycle having 1 to 3 N, O and/or S atoms, which is unsubstituted ormono- or disubstituted by Hal, NH₂, A and/or ═O (carbonyl oxygen), or apharmaceutically acceptable salt or tautomer thereof.
 13. A compoundaccording to claim 1, in which Het denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl, tetrahydro-pyridazine, imidazolidinyl,benzoxazolyl, or benzo-2,1,3- thiadiazolyl, each of which isunsubstituted or mono- or disubstituted by A, NH₂, and/or ═O (carbonyloxygen), or a pharmaceutically acceptable salt or tautomer thereof. 14.A compound according to claim 1, in which A denotes unbranched orbranched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replacedby F and/or Cl, or a pharmaceutically acceptable salt or tautomerthereof.
 15. A compound of formula I

in which R¹ denotes a bicyclic unsaturated or aromatic heterocycle,which is one of the following groups

which is unsubstituted or mono-, di- or trisubstituted by A, Ar, SR,NR₂, Hal, NO₂, CN, (CR₂)_(n)[X(CR₂)_(n)]_(p)—Y, CONR₂, OR⁵ and/or ═O(carbonyl oxygen), R² denotes H or A, R³ denotes H, R⁴ denotes H, Xdenotes O, NR or CR₂, Y denotes OR or NR₂, R⁵ denotes H or unbranched orbranched alkyl having 1, 2, 3 or 4 C atoms, in which 1-5 H atoms may bereplaced by F, K denotes CO or CH₂, E denotes COOCH₂, COOCH₂CH₂,SO₂CH₂CH₂, CONHCH₂, COCH₂O or COCH₂CH₂, R denotes H or methyl, W denotesAr or Het, G denotes CH or N, Ar denotes phenyl, naphthyl or biphenyl,each of which is unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by Hal, A, (CR₂)_(n) Het, SA and/or OA, Het denotespiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl,indolyl, benzo-1,3-dioxolyl, indazolyl tetrahydro-pyridazine,imidazolidinyl benzoxazolyl or benzo-2,1,3-thiadiazolyl, each of whichis unsubstituted or mono- or disubstituted by A, NH₂, and/or ═O(carbonyl oxygen), A denotes unbranched or branched alkyl having 1-10 Catoms, in which 1-7 H atoms may be replaced by F and/or Cl, m denotes 1,n denotes 1, p denotes 1, and Hal denotes F, Cl, Br or I, or apharmaceutically acceptable salt or tautomer thereof.
 16. A compoundwhich is one of the following compounds No. Name and/or structure “A1” 4-Chlorobenzyl 4-[4-(1H-benzotriazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A2”  4-Chlorobenzyl 4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl-carbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A3”  4-Trifluoromethylsulfanylbenzyl 4-[4-(1H-benzotriazol-5-yl-carbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A4”  4-Trifluoromethoxybenzyl 4-[4-(1H-benzotriazol-5-yl-carbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A5”  4-Trifluoromethylbenzyl 4-[4-(1H-benzotriazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A6”  4-Fluorobenzyl4-[4-(1H-benzotriazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A7”  4-Methylbenzyl4-[4-(1H-benzotriazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A8”  4-Ethylbenzyl4-[4-(1H-benzotriazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A9”  3,5-Dichlorobenzyl4-[4-(1H-benzotriazol-5-ylcarbamoyl)-thiazol-2-yl]piperazine-1-carboxylate “A10”4-Trifluoromethylsulfanylbenzyl 4-[4-(2-oxo-2,3-dihydro-benzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate “A11”4-Trifluoromethoxybenzyl 4-[4-(2-oxo-2,3-dihydro-benzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate “A12”4-Trifluoromethylbenzyl 4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate 133,5-Dichlorobenzyl 4-{5-[(1H-benzotriazol-5-ylamino)methyl]-4-methylthiazol-2-yl}piperidine-1-carboxylate “A13” 4-Fluorobenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A14” 4-Methylbenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A15” 4-Ethylbenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A16”3,5-Dichlorobenzyl 4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A17”4-tert-Butylbenzyl 4-[4-(1H-benzotriazol-5-ylcarbamoyl)-thiazol-2-yl]piperazine-1-carboxylate “A18” 4-tert-Butylbenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A19” 4-Phenylbenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate “A20”4-Morpholin-4-ylmethylbenzyl 4-[4-(2-oxo-2,3-dihydro-benzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate

“A21” 4-Trifluoromethylsulfanylbenzyl 4-[4-(1H-indazol-5-yl-carbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A22” 4-Trifluoromethylsulfanylbenzyl 4-[4-(1H-indo1-5-yl-carbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A23” 4-Trifluoromethylsulfanylbenzyl 4-[4-(benzothiazol-6-yl-carbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A24” 4-Trifluoromethylsulfanylbenzyl 4-[4-(benzo-1,2,5-thiadiazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1-carboxylate

“A25” 4-Trifluoromethylsulfanylbenzyl 4-[4-(2-trifluoromethyl-1H-benzimidazol-5-ylcarbamoyl)thiazol-2-yl]piperazine-1- carboxylate

“A26” N-(1H-Benzotriazol-5-yl)-2-{4-[2-(4-chlorophenoxy)acetyl]-piperazin-1-yl}thiazole-4-carboxamide

“A27” N-(1H-Benzotriazol-5-yl)-2-{4-[2-(4-chlorophenylamino)-acetyl]piperazin-1-yl}thiazole-4-carboxamide

“A28” 4-Chlorobenzyl 4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate

“A29” 4-Chlorobenzyl 4-[4-(1H-benzotriazol-5-ylcarbamoyl)thiazol-2-yl]piperidine-1-carboxylate

“A30” 4-Isopropylbenzyl 4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A31” 3,4-Dimethylbenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A32” 3,4-Dimethylbenzyl4-[4-(1H-benzotriazol-5-ylcarbamoyl)-thiazol-2-yl]piperidine-1-carboxylate “A33” 2,4-Dichlorobenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A34” 2,4-Dichlorobenzyl4-[4-(1H-benzotriazol-5-ylcarbamoyl)-thiazol-2-yl]piperidine-1-carboxylate “A35” 3,5-Dichlorobenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A36”4-Trifluoromethylsulfanylbenzyl 4-[4-(2-oxo-2,3-dihydro-benzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine-1- carboxylate “A37”4-Trifluoromethylbenzyl 4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-ylcarbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A38” 4-Chlorobenzyl4-{4-[(1H-benzotriazol-5-ylamino)methyl]-thiazol-2-yl}piperidine-1-carboxylate

“A39” 4-Chlorobenzyl 4-{5-[(1H-benzotriazol-5-ylamino)methyl]-4-methylthiazol-2-yl}piperidine-1-carboxylate

“A40” N-(4-Trifluoromethoxybenzyl)-4-[4-(1H-benzotriazol-5-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxamide

“A41” N-(1H-Benzotriazol-5-yl)-2-{1-[2-(4-chlorophenoxy)acetyl]-piperidin-4-yl}thiazole-4-carboxamide

“A42” N-(1H-Benzotriazol-5-yl)-2-{1-[3-(4-trifluoromethylphenyl)-propionyl]piperidin-4-yl}thiazole-4-carboxamide

“A43” N-(1H-Benzotriazol-5-yl)-2-[1-(2-phenylethylsulfonyl)-piperidin-4-yl]thiazole-4-carboxamide

“A44” 4-Chlorobenzyl 4-[4-(2-trifluoromethyl-1H-benzimidazol-5-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “A45” 4-Chlorobenzyl4-[4-(1H-indazol-5-ylcarbamoyl)thiazol-2-yl]- piperidine-1-carboxylate“A46” N-(2-Trifluoromethyl-1H-benzimidazol-5-yl)-2-{1-[3-(4-trifluoromethylphenyl)propionyl]piperidin-4-yl}thiazole-4- carboxamide

“A47” N-(2-Oxo-2,3-dihydrobenzoxazol-6-yl)-2-{1-[3-(4-trifluoromethylphenyl)propionyl]piperidin-4-yl}thiazole-4- carboxamide

“A48” 1-{4-[4-[(1H-Benzotriazol-5-ylamino)methyl]thiazol-2-yl}-piperidin-1-yl)-3-(4-trifluoromethylphenyl)propan-1-one

“A49” 3,5-Dichlorobenzyl 4-{4-[(1H-benzotriazol-5-ylamino)methyl]-thiazol-2-yl}piperidine-1-carboxylate

“A50” 4-Trifluoromethylsulfanylbenzyl 4-{5-[(1H-benzotriazol-5-yl-amino)methyl]-4-methylthiazol-2-yl}piperidine-1-carboxylate

“A51” 3,5-Dichlorobenzyl 4-[4-(benzothiazol-6-ylcarbamoyl)thiazol-2-yl]piperidine-1-carboxylate

“A52” N-(Benzothiazol-6-yl)-2-{1-[3-(4-trifluoromethylphenyl)-propionyl]piperidin-4-yl}thiazole-4-carboxamide

“A53” N-(2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2-{1-[3-(4-trifluoromethylphenyl)propionyl]piperidin-4-yl}thiazole-4- carboxamide

“A54” 4-Chlorobenzyl 4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbamoyl)thiazol-2-yl]piperidine-1-carboxylate

“A55” 3,5-Dichlorobenzyl 4-[4-(1H-benzimidazol-5-ylcarbamoyl)-thiazol-2-yl]piperidine-1-carboxylate

“A56” 3,5-Dichlorobenzyl 4-[5-(1H-benzotriazol-5-ylcarbamoyl)-4-methylthiazol-2-yl]piperidine-1-carboxylate

or a pharmaceutically acceptable salt or tautomer thereof.
 17. Acompound which is one of the following compounds “B1” 4-Chlorobenzyl4-[4-(3-amino-1H-indazol-6-ylcarbamoyl)-thiazol-2-yl]piperidine-1-carboxylate “B2” 3,5-Dichlorobenzyl4-[4-(3-amino-1H-indazol-6-yl-carbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B3” 4-Chlorobenzyl4-[4-(3-imidazol-1-ylpropylcarbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B4” 4-Chlorobenzyl4-{4-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)phenylcarbamoyl]thiazol-2-yl}piperidine-1- carboxylate“B5” 4-Chlorobenzyl 4-{4-[3-(4-methyl-2,5-dioxoimidazolidin-4-yl)-propylcarbamoyl]thiazol-2-yl}piperidine-1-carboxylate “B6”4-Chlorobenzyl 4-[4-(2-imidazol-1-ylethylcarbamoyl)thiazol-2-yl]piperidine-1-carboxylate “B7”N-(3-Amino-1H-indazol-5-yl)-2-{1-[3-(4-trifluoromethyl-phenyl)propionyl]piperidin-4-yl}thiazole-4-carboxamide “B8”4-Chlorobenzyl 4-{4-[2-(2-amino-1H-benzimidazol-5-yl)-ethylcarbamoyl]thiazol-2-yl}piperidine-1-carboxylate “B9” 4-Chlorobenzyl4-[4-(3-amino-1H-indazol-5-ylcarbamoyl)-thiazol-2-yl]piperidine-1-carboxylate “B10” 3,5-Dichlorobenzyl4-{4-[2-(1H-imidazol-4-yl)-ethylcarbamoyl]thiazol-2-yl}piperidine-1-carboxylate “B11”4-Chlorobenzyl 4-{4-[3-(3-oxo-3H-pyrazol-4-yl)-propylcarbamoyl]thiazol-2-yl}piperidine-1-carboxylate “B12”3,5-Dichlorobenzyl 4-[4-(2-imidazol-1-ylethylcarbamoyl)-thiazol-2-yl]piperidine-1-carboxylate “B13” 4-Chlorobenzyl4-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-thiazol-2-yl]piperidine-1-carboxylate “B14”N-(4-Chlorophenyl)-4-[4-(1H-benzotriazol-5-ylcarbamoyl)-thiazol-2-yl]pipendine-1-carboxamide “B16” 3,5-Dichlorobenzyl4-{4-[(1H-benzotriazol-5-ylcarbamoyl)-methyl]-5-methylthiazol-2-yl}pipendine-1-carboxylate

or a pharmaceutically acceptable salt or tautomer thereof.
 18. A processfor preparing a compound of formula I of claim 1 or a pharmaceuticallyacceptable salt or tautomer thereof, comprising reacting a compound offormula II

in which R¹, R², R³, R⁴, G and K have the meanings indicated for thecompound of formula I, with a compound of formula IIIL-E-W  III in which E and W have the meanings indicated for the compoundof formula, and L denotes Cl, Br, I or a free or reactively functionallymodified OH group, and/or converting a base or acid of a compound offormula I into one of its salts.
 19. A pharmaceutical compositioncomprising at least one compound of formula I according to claim 1 or apharmaceutically acceptable salt or tautomer thereof and one or morepharmaceutically acceptable excipients and/or adjuvants.